CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I

Eur J Immunol. 2003 Feb;33(2):494-501. doi: 10.1002/immu.200310025.

Abstract

We have previously shown that the CC-chemokine 1-309 (CCL1) protects mouse thymic lymphomas against corticoid-induced apoptosis. Here, we analyzed the signal transduction pathways involved in this activity on BW5147 lymphoma. Inhibition of the CCL1 activity by pertussis toxin suggested the involvement of a G protein-coupled chemokine receptor. The role of CCR8 was supported by the observation that vMIP-I, another CCR8-ligand identified from the genome of a T cell transforming herpes virus, shared CCL1 anti-apoptotic activity. In addition to CCR8, BW5147 cells also expressed the CXCR4 receptor but its ligand, SDF-1 (CXCL12) showed only a modest anti-apoptotic activity. Other chemokines acting on CCR2, CCR4 and CCR5 failed to protect against apoptosis and to induce BW5147 chemotaxis, suggesting that these receptors were not functionally expressed. By contrast, both CCL1 and vMIP-I up-regulated ERK1/2 MAPK phosphorylation in BW5147 cells. Further analysis demonstrated that CCL1 activates the MAPK pathway in CCR8-transfected CHO cells. The implication of this pathway was confirmed by the fact that PD98059, an inhibitor of MEK kinases, as well as a dominant negative isoform of the M-RAS protein specifically blocked the anti-apoptotic activity of CCL1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • CHO Cells
  • Chemokine CCL1
  • Chemokine CXCL12
  • Chemokines, CC / antagonists & inhibitors
  • Chemokines, CC / genetics
  • Chemokines, CC / physiology*
  • Chemokines, CXC / pharmacology
  • Chemotaxis / drug effects
  • Cricetinae
  • Cricetulus
  • Dexamethasone / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Dominant
  • Herpesvirus 8, Human / physiology
  • Humans
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System / physiology*
  • Macrophage Inflammatory Proteins / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / physiology
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Pertussis Toxin / pharmacology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Receptors, CCR8
  • Receptors, CXCR4 / physiology
  • Receptors, Chemokine / biosynthesis
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / physiology*
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Viral Proteins / physiology*
  • ras Proteins / physiology*

Substances

  • CCL1 protein, human
  • CCR8 protein, human
  • CXCL12 protein, human
  • Ccl1 protein, mouse
  • Chemokine CCL1
  • Chemokine CXCL12
  • Chemokines, CC
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • Enzyme Inhibitors
  • Flavonoids
  • Macrophage Inflammatory Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, CCR8
  • Receptors, CXCR4
  • Receptors, Chemokine
  • Recombinant Fusion Proteins
  • Viral Proteins
  • vMIP-1 protein, Human herpesvirus 8
  • Dexamethasone
  • Pertussis Toxin
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • Mras protein, mouse
  • Monomeric GTP-Binding Proteins
  • ras Proteins
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one